Seasonal influenza (flu) virus, an NIAID category C priority pathogen, causes widespread infection, resulting in at least 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide. Young children and elderly or immunocompromised individuals are typically at greater risk of severe illness or death from influenza. Newly emerging strains can result in influenza pandemics with much higher mortality rates, even in young healthy adults. To address this threat to public health, annual universal vaccination is recommended for all individuals aged over 6 months in the US. Current vaccines include inactivated trivalent split or subunit and live attenuated vaccine, both of which have the drawback that they must be grown using laborious methods in eggs and reformulated every year based on the influenza strains predicted to be prevalent in the next flu season. However, the major disadvantage of these vaccines is a surprising lack of effectiveness, which was highlighted in a recent meta analysis of influenza vaccine (live and inactivated) in the US. Even in the recent 2012-13 season in which the vaccine was well-matched to circulating strains, only 59% efficacy across the population and a meager 9% efficacy in the elderly was achieved, casting doubt on the long-standing belief that a close match between the vaccine virus strains and circulating strains results in high effectiveness. There is an urgent need for the development of highly effective and cross-protective influenza vaccines and new rapid methods of manufacturing. To meet this need FluGen has developed a novel vaccine virus (M2SR) based on the deletion of the M2 gene. This deletion in the viral genome allows for single replication of the vaccine virus in the host and production of viral proteins, which induces strong cross-protective immunity without the generation of progeny virions (shedding), a goal unmet by current vaccine strategies. The M2SR is a platform backbone virus that can be modified to encode the viral antigens from any influenza strain and is produced in a novel cell culture system, avoiding the use of eggs. We hypothesize that M2SR will provide safe, highly effective, broad spectrum, long-lasting protection against influenza. Our preliminary data support this hypothesis and show that the vaccine elicits strong systemic and mucosal immune responses and provides effective cross-reactive protection against lethal challenge with influenza. We will test this hypothesis in 3 Specific Aims: Aim 1. To determine the efficacy of protection afforded by the M2SR vaccine. We will further investigate the efficacy and longevity of protection against homologous and heterologous viral challenge. Aim 2. To determine whether M2SR has any pathological effects. Lung histology and the inflammatory response will be assessed after vaccination and challenge. Aim 3. To determine the mechanism of heterologous protection. We will investigate the role of virus-specific T and B cell responses in cross-protection. These studies will provide a comprehensive pre-clinical evaluation of the efficacy and safety of the M2SR vaccine.